miniaturization in electronic technologyme.jhu.edu/thwang/notes/introduction-biomems.pdf · eniac:...

BioSensing & BioMEMS 530/580.672 Jeff Wang Johns Hopkins University

ENIAC: the "Electronic Numerical Integrator and

Calculator“, 1943

ENIAC filled a 20 by 40 feet room, weighed 30 tons,

and used more than 18,000 vacuum tubes.

Miniaturization in Electronic Technology

A8 Chip, 2014

>109 transistor

iPhone 6

BioSensing & BioMEMS 530/580.672 Jeff Wang Johns Hopkins University 2

Savings in time & cost

Less materials and samples

Short processing time

Disposable

Parallel processing

Integration/Automation

Why Being Small ?

• Laminar Flow

• High surface to volume ratio

High single-to-noise ratio in transuding signals

• Small thermal mass

• Strong fields such as electric fields

Gain from the unique

microscopic features


Spacecraft Human Organ Tissue Cell DNA

>100 m 1 m 10-2 m 10-6 m 10-9 m

Micro/Nano Technology

Length Scale Matching

• Manipulation of

molecules and cells

• High resolution /

sensitivity

(Kim)

(Wang)

Why Being Small ?

e.g. to facilitate single-molecule diagnostics,

study of single-cell biology


Classes of BioMEMS

(Bio-MicroElectroMechanicalSystem)

Microfluidics & Microfluidic Devices

Biosensors and Bioelectronics

Neural Interface Devices

Chromatography /Electrophoresis Devices

Microsurgical Tools

Bioreactors

Tissue Engineering Devices

Molecule /Cell Handling Devices

Implantable Devices, Drug Delivery Devices


(Sandia)

Examples of MEMS Devices

Spider mite on gears

Micro-mirrors


Projector

(Texas Instruments)

(Analog Device)

Air Bag Sensor

Bubble Inkjet

(HP)

Examples of Industrial MEMS Devices

Motion & Orientation sensor (Wii)

(Nintendo)


Apple iPhone 6

6-axis Gyro/Accel (Invensense)

3-axis Accelerometer(Bosch)

3-axis Magnetometer (AKM)

3 microphones (Knowles)

Pressure Sensors (Bosch)


MEMS Is Everywhere in Your Daily Life

Trillions of MEMS sensors coming soon !

Internet of Things (IoT)


Capillary Electrophoresis


Micromachined Capillary Electrophoresis (m-CE)

• High throughput

• Low volume

• Rapid analysis (Ra Mathies, PNAS 2006)

• Integrated with thermal

cycling and CE for

Sanger sequencing

• Off-chip optical detection


Thermal Cycling for Polymerase Chain Reaction (PCR)

PCR is an expensive and time-consuming technique


Continuous-flow Micro PCR

(A. Manz, Science 2002)

(M.A. Burns U Mich, Science)

• PCR reaction

• Gel electrophoresis

• Microfluidics

• On-line electrical detector

Integration of CE and m-PCR

http://www.sciencemag.org/content/vol280/issue5366/images/large/se2186518001.jpeg


Microfluidic Digital PCR : Nanoliter-sized PCR arrays

(J.R. Leadbetter, Science 2006)

• 1176 chamber

• 6.25 nL each chamber


Droplet Digital PCR: Picoliter-sized PCR arrays

(T. Rane, Lab Chip, 2015)

0 2 4 6 8 100

1000

2000

Ph

oto

n C

ou

nts

per

100

use

c

Calcein Channel

0 2 4 6 8 100

500

1000

Time (sec)

ROX channel

2.35 2.4 2.450

500

1000

1500

Ph

oto

n C

ou

nts

per

100

use

c

Calcein Channel

2.35 2.4 2.450

500

1000

Time (sec)

ROX channel


Analysis of Single Cells

(R. Zare, Scinece 2006)

Single-Molecule

Detection

Preparation of a

single cell

http://www.sciencemag.org/content/vol315/issue5808/images/large/315_81_F1.jpeg


Laminar Flow-Based Assay

(P. Yager)

• Laminar flow – initiate reaction

• Diffusion-based analysis

T-Sensor

Separation

Rapid Mixing


Flied Flow Fraction-DEP cell sorter

( U. Texas, Houston)

• Field flow fraction using

DEP force


Free Solution Hydrodynamic Separation


Nano Fluidics

100-nm-wide nanochannel array

Stretch of l DNA (48.6 kbp)fragment

DNA is driven by E-field

(R. Austin)

http://www.pnas.org/content/vol101/issue30/images/large/zpq0280453990002.jpeg

http://www.pnas.org/content/vol101/issue30/images/large/zpq0280453990004.jpeg


Digital Microfluidics

• Pump-free and valve-free

• Each sample and reagent is

individually addressable

• Array-based analysis


Integrated DNA Preparation and PCR Detection

Using Silica Superparamagnetic Particles (SSP) as a solid phase within droplets

Lysis/Binding buffer

Washing buffer 1

Cell lysis DNA purification

& concentration PCR reaction DNA amplification

(thermal cycling)

Centralized & manual tube based PCR

detection

Sample

In Answer

Out

Sample 1

Sample 2


Surface topology assisted SSP and droplet

manipulation

a)

SS

P p

lug

Su

rfa

ce

ele

va

tio

n

a)

b)

Surface elevation

SSP plug

Drops in Air

Drops in Oil

(Y Zhang, Lab Chip 2011)


0 5 10 15 20 25 30 350

400

800

1200

1600

Flu

ore

sce

nce

In

ten

sit

y (

AU

)

Cycle (n)

a) b)

40 50 60 70 80 90 1000.0

0.2

0.4

0.6

0.8

1.0

0.00

0.02

0.04

0.06

0.08

0.10 Fluorescence

-dF

/dT

No

rmalize

d F

luo

rescen

ce In

ten

sit

y

Temperature (Celsius)

Negative first derivative

On-Chip Real-Time PCR Detection

0 10 20 30 40900

1000

1100

1200

1300

1400

1500

Flu

ore

scen

ce I

nte

nsit

y (

AU

)

Cycle (n)

Detection of E coli 16S gene from cell culture

Marker Amplicon

100bp

150bp

200bp

250bp

300bp

Detection of Rsf-1 marker from whole blood

0 5 10 15 20 25 30 350

400

800

1200

1600

Flu

ore

sc

en

ce

In

ten

sit

y (

AU

)

Cycle (n)

a) b)

40 50 60 70 80 90 1000.0

0.2

0.4

0.6

0.8

1.0

0.00

0.02

0.04

0.06

0.08

0.10 Fluorescence

-dF

/dT

No

rmalized

Flu

ore

scen

ce In

ten

sit

y

Temperature (Celsius)

Negative first derivative


Features

• Monodisperse droplets of

sizes ranging from nL-pL

• High speed droplet

generation of > kHz

Potential applications

• Low-cost & High throughput

screening

• Biochemical synthesis

• Digital PCR

• Single-cell analysis

24 24

Microfluidic Droplet Technology for High-Throughput Analysis


Droplet Microfluidics for Monitoring of Kinetics


DNA Microarrays

Affymetrix

• Fabricated with lithographic

technique

• cDNA array

• Gene expression profiling

• Relative fluorescence

measurement


Neural Probe/ Neuro Implant

• Neuro-circuit interaction – neuro-recoding

• Prosthesis research

• Chemical delivery

• Issues with long term implant – bio compatibility


Tissue Engineering / Cell Patterning • Patterning cells using microfluidics

• Control of microenvironments using microfluidics

• Single-cell (controlled small number of cells) patterning

• High-throughput search for right cell conditions for controlling cell growth,

differentiation, apoptosis)

( Whitesides)


Corneal Microtissue Culture

( C. Puleo, Lab Chip. 2009)

miniaturization in electronic technologyme.jhu.edu/thwang/notes/introduction-biomems.pdf · eniac:...

Documents